US2022274921A1PendingUtilityA1
Phenyl compounds and pharmaceutical compositions thereof, and their therapeutic applications
Est. expiryJul 11, 2039(~13 yrs left)· nominal 20-yr term from priority
Inventors:Nazneen Dewji
A61P 25/28C07C 311/21C07C 2601/14A61P 27/02A61P 25/00A61P 25/16
43
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Claims
Abstract
Provided herein are compounds, for example, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
wherein:
each R 1 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d ,
—NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a ,
—C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c ,
—S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
X is —SO 2 — and Y is —N(R N )— or —CR X R Y —; or X is —N(R N )— or —CR X R Y — and Y is —SO 2 —;
each R N is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and R P is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or
each R N is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and R P is hydrogen;
m is an integer of 0, 1, 2, 3, or 4; and
each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclyl; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from (a) deuterium, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) —C(O)R a , —C(O)OR a ,
—C(O)NR b R c , —C(O)SR a , —C(NR a )NR b R c , —C(S)R a , —C(S)OR a , —C(S)NR b R c , —OR a , —OC(O)R a ,
—OC(O)OR a , —OC(O)NR b R c , —OC(O)SR a , —OC(═NR a )NR b R c , —OC(S)R a , —OC(S)OR a , —OC(S)NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d ,
—NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(O)SR d , —NR a C(═NR d )NR b R c , —NR a C(S)R d , —NR a C(S)OR d , —NR a C(S)NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ;
wherein each Q a is independently selected from the group consisting of (a) deuterium, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g ,
—C(O)SR e , —C(NR e )NR f R g , —C(S)R e , —C(S)OR e , —C(S)NR f R g , —OR e , —OC(O)R e , —OC(O)OR e ,
—OC(O)NR f R g , —OC(O)SR e , —OC(═NR e )NR f R g , —OC(S)R e , —OC(S)OR e , —OC(S)NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f ,
—NR e C(O)NR f R g , —NR e C(O)SR f , —NR e C(═NR h )NR f R g , —NR e C(S)R h , —NR e C(S)OR f , —NR e C(S)NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.
2 . The compound of claim 1 , wherein:
each R 1 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a ,
—C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c ,
—S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
R 2 , R 5 , and R 6 are each independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d ,
NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c ,
NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
R 3 is (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d ,
—NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; and
R 4 is hydrogen, deuterium, cyano, or fluoro;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.
3 . The compound of claim 1 or 2 , wherein the compound is a compound of Formula II:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
4 . The compound of claim 1 or 2 , wherein the compound is a compound of Formula III:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
5 . The compound of claim 1 or 2 , wherein the compound is a compound of Formula IV:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
6 . The compound of any one of claims 1 to 5 , wherein X is —SO 2 —.
7 . The compound of any one of claims 1 to 6 , wherein Y is —NR N —.
8 . The compound of claim 1 or 2 , wherein the compound is a compound of Formula XIII:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
9 . The compound of claim 1 or 2 , wherein the compound is a compound of Formula XIV:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
10 . The compound of claim 1 or 2 , wherein the compound is a compound of Formula XV:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
11 . The compound of claim 1 or 2 , wherein the compound is a compound of Formula XV:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
12 . The compound of any one of claims 7 to 11 , wherein R N is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q.
13 . The compound of any one of claims 7 to 12 , wherein R N is C 1-6 alkyl, substituted with one or more substituents Q.
14 . The compound of any one of claims 7 to 13 , wherein R N is hydrogen, —CHR 1a —O—C(O)R 1c , —CHR 1a —O—C(O)OR 1c , or —CHR 1a —O—C(O)NR 1b R 1c .
15 . The compound of claim 14 , wherein R N is —CHR 1a —O—C(O)R 1c .
16 . The compound of claim 14 , wherein R N is —CHR 1a —O—C(O)OR 1c .
17 . The compound of any one of claims 14 to 16 , wherein R 1a is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q.
18 . The compound of any one of claims 14 to 17 , wherein R 1c is C 1-6 alkyl or C 3-10 cycloalkyl, each optionally substituted with one or more substituents Q.
19 . The compound of any one of claims 7 to 11 , wherein R N is hydrogen, pivalyloxymethyl, or 1-((cyclohexyloxy)carbonyloxy)ethyl.
20 . The compound of any one of claims 1 to 6 , wherein Y is —NH—.
21 . The compound of any one of claims 1 to 6 , wherein Y is —CR X R Y —.
22 . The compound of any one of claims 1 to 6 and 21 , wherein Y is —CH 2 —.
23 . The compound of any one of claims 1 to 5 , wherein Y is —SO 2 —.
24 . The compound of any one of claims 1 to 5 and 23 , wherein X is —NR N —.
25 . The compound of claim 24 , wherein R N is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q.
26 . The compound of claim 24 , wherein R N is C 1-6 alkyl, substituted with one or more substituents Q.
27 . The compound of claim 24 , wherein R N is hydrogen, —CHR 1a —O—C(O)R 1c , —CHR 1a —O—C(O)OR 1c , or —CHR 1a —O—C(O)NR 1b R 1c .
28 . The compound of claim 27 , wherein R N is —CHR 1a —O—C(O)R 1c .
29 . The compound of claim 27 , wherein R N is —CHR 1a —O—C(O)OR 1c .
30 . The compound of any one of claims 27 to 29 , wherein R 1a is hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q.
31 . The compound of any one of claims 27 to 30 , wherein R 1c is C 1-6 alkyl or C 3-10 cycloalkyl, each optionally substituted with one or more substituents Q.
32 . The compound of claim 24 , wherein R N is hydrogen, pivalyloxymethyl, or 1-((cyclohexyloxy)carbonyloxy)ethyl.
33 . The compound of any one of claims 1 to 5 and 23 , wherein X is —NH—.
34 . The compound of any one of claims 1 to 5 and 23 , wherein X is —CR X R Y —.
35 . The compound of claim 34 , wherein Y is —CH 2 —.
36 . The compound of any one of claims 1 to 35 , wherein each R 1 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a ,
—C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , C 1-6 alkoxy, —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d ,
—NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c ,
—NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; where the alkoxy is optionally substituted with one or more substituents Q.
37 . The compound of any one of claims 1 to 36 , wherein each R 1 is independently halo or C 1-6 alkyl, optionally substituted with one or more substituents Q.
38 . The compound of any one of claims 1 to 37 , wherein each R 1 is fluoro or methyl, optionally substituted with one or more substituents Q.
39 . The compound of any one of claims 1 to 38 , wherein m is an integer of 1.
40 . The compound of any one of claims 1 to 38 , wherein m is an integer of 0.
41 . The compound of any one of claims 1 to 40 , wherein R 2 is hydrogen.
42 . The compound of any one of claims 1 to 41 , wherein R 4 is hydrogen.
43 . The compound of any one of claims 1 to 42 , wherein R 3 is (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)—C 1-6 alkyl, —C(O)OR 1a , —C(O)NHR 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d ,
—NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c ,
—NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is independently and optionally substituted with one or more substituents Q.
44 . The compound of any one of claims 1 to 43 , wherein R 3 is nitro, C 1-6 alkyl, —OR 1a , or —NR 1a S(O) 2 R 1d ; wherein the alkyl is optionally substituted with one or more substituents Q.
45 . The compound of any one of claims 1 to 44 , wherein R 3 is nitro, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylsulfonamido; wherein each alkyl and alkoxy is optionally substituted with one or more substituents Q.
46 . The compound of any one of claims 1 to 45 , wherein R 3 is nitro, trifluoromethyl, methoxy, or methylsulfonamido.
47 . The compound of any one of claims 1 to 46 , wherein R 5 is hydrogen or —OR 1a .
48 . The compound of any one of claims 1 to 47 , wherein R 5 is hydrogen or C 1-6 alkoxy; wherein the alkoxy is optionally substituted with one or more substituents Q.
49 . The compound of any one of claims 1 to 48 , wherein R 5 is hydrogen or methoxy.
50 . The compound of any one of claims 1 to 49 , wherein R 6 is hydrogen, C 1-6 alkyl, or —OR 1a .
51 . The compound of any one of claims 1 to 50 , wherein R 6 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy; wherein the alkyl and alkoxy are each optionally substituted with one or more substituents Q.
52 . The compound of any one of claims 1 to 51 , wherein R 6 is hydrogen, methyl, or methoxy.
53 . The compound of any one of claims 1 to 52 , wherein:
each R 1 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a ,
—C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , C 1-6 alkoxy, —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c ,
—S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
R 2 and R 4 are each hydrogen;
R 3 is (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)—C 1-6 alkyl, —C(O)OR 1a , —C(O)NHR 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1b , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c ,
—OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )R 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; and
R 5 and R 6 are each independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c ,
—C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c ,
—S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is independently and optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.
54 . The compound of any one of claims 1 to 52 , wherein:
each R 1 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a ,
—C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , C 1-6 alkoxy, —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c ,
—S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
R 2 and R 4 are each hydrogen;
R 3 is nitro, C 1-6 alkyl, —OR 1a , or —NR 1a S(O) 2 R 1d ;
R 5 is hydrogen or —OR 1a ;
R 6 is hydrogen, C 1-6 alkyl, or —OR 1a ; and
m is an integer of 0, 1, 2, or 3;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is independently and optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.
55 . The compound of any one of claims 1 to 52 , wherein:
each R 1 is independently halo or C 1-6 alkyl;
R 2 and R 4 are each hydrogen;
R 3 is nitro, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylsulfonamido;
R 5 is hydrogen or C 1-6 alkoxy;
R 6 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy; and
m is an integer of 0, 1, or 2;
wherein each alkyl, alkoxy, and C 1-6 alkylsulfonamido is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.
56 . The compound of any one of claims 1 to 52 , wherein:
R 1 is fluoro or methyl;
R 2 and R 4 are each hydrogen;
R 3 is nitro, trifluoromethyl, methoxy, or methylsulfonamido;
R 5 is hydrogen or methoxy;
R 6 is hydrogen, methyl, or methoxy; and
m is an integer of 0 or 1.
57 . The compound of any one of claims 1 to 52 , wherein the compound is:
(pivaloyloxy)methyl 3-(N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)-benzoate;
1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-(N-(2-methyl-5-(trifluoromethyl)-phenyl)sulfamoyl)benzoate; or
(pivaloyloxy)methyl 3-(N-(2-methyl-5-(trifluoromethyl)phenyl)-N-((pivaloyl-oxy)methyl)sulfamoyl)benzoate;
or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
58 . A pharmaceutical composition comprising the compound of any one of claims 1 to 57 , and a pharmaceutically acceptable excipient.
59 . The pharmaceutical composition of claim 58 , wherein the pharmaceutical composition is in single dosage form.
60 . The pharmaceutical composition of claim 58 or 59 , wherein the pharmaceutical composition is in an oral, parenteral, or intravenous dosage form.
61 . The pharmaceutical composition of claim 60 , wherein the composition is in an oral dosage form.
62 . The pharmaceutical composition of claim 61 , wherein the oral dosage form is a tablet, capsule, or solution.
63 . The pharmaceutical composition of any one of claims 58 to 62 , further comprising a second therapeutic agent.
64 . A method of treating one or more symptoms of a neurodegenerative disease in a subject, comprising administering to the subject the compound of any one of claims 1 to 57 or the pharmaceutical composition of any one of claims 58 to 63 .
65 . The method of claim 64 , wherein the neurodegenerative disease is Alzheimer's disease.
66 . The method of claim 64 or 65 , wherein the neurodegenerative disease is Stage 1 Alzheimer's disease.
67 . The method of claim 64 or 65 , wherein the neurodegenerative disease is Stage 2 Alzheimer's disease.
68 . The method of claim 64 or 65 , wherein the neurodegenerative disease is Stage 3 Alzheimer's disease.
69 . The method of claim 64 or 65 , wherein the neurodegenerative disease is Stage 4 Alzheimer's disease.
70 . The method of claim 64 or 65 , wherein the neurodegenerative disease is Stage 5 Alzheimer's disease.
71 . The method of claim 64 or 65 , wherein the neurodegenerative disease is Stage 6 Alzheimer's disease.
72 . The method of claim 64 or 65 , wherein the neurodegenerative disease is Stage 7 Alzheimer's disease.
73 . The method of claim 64 , wherein the neurodegenerative disease is Parkinson's disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, or dementia.
74 . A method of treating one or more symptoms of a disorder, disease, or condition in a subject, comprising administering to the subject the compound of any one of claims 1 to 57 or the pharmaceutical composition of any one of claims 58 to 63 ; wherein the disorder, disease, or condition is an ocular disorder or Downs syndrome.
75 . A method of inhibiting the production of amyloid β in a subject, comprising administering to the subject the compound of any one of claims 1 to 57 or the pharmaceutical composition of any one of claims 58 to 63 .
76 . A method of attenuating the amyloid β level in a subject, comprising administering to the subject the compound of any one of claims 1 to 57 or the pharmaceutical composition of any one of claims 58 to 63 .
77 . The method of claim 75 or 76 , wherein the amyloid β is amyloid β40.
78 . The method of claim 75 or 76 , wherein the amyloid β is amyloid β42.
79 . A method of inhibiting the production of amyloid β in a cell, comprising contacting the cell with the compound of any one of claims 1 to 57 .
80 . The method of claim 79 , wherein the amyloid β is amyloid β40.
81 . The method of claim 79 , wherein the amyloid β is amyloid β42.Join the waitlist — get patent alerts
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